tbuckley/cabot-search huggingface dataset:
Abstract 3319: Purified poloxamer 188 mitigates radiation-induced lung toxicity
Authors: Sarah G. Dennis-Little, Wilfred Ngwa, Marikki Laiho, Graham Warren, Michael J. Yost
Journal: Cancer Research (2022)

Abstract The dose-limiting factor in radiation therapy (RT) is damage to healthy tissues, which presents as radiation-induced lung toxicity (RILT). Acute RILT, pneumonitis, is an early inflammatory-driven toxicity that develops within weeks to months following RT. Purified poloxamer 188 (PP188) is a triblock copolymer that associates with and protects cell membranes from oxidative insult, minimizing secondary inflammatory damage. This study aimed to investigate the effects of PP188 to mitigate the onset of acute radiation pneumonitis in a rat model of RILT, and to test the effect of PP188 on the efficacy of RT on tumor growth of a syngeneic CT26.WT murine colon carcinoma in Balb/c mice. To evaluate the efficacy of PP188 to mitigate RILT in healthy tissues, Sprague Dawley rats were given 200mg/kg PP188 or vehicle via IV 1hr prior to a single dose of partial volume (6mm) 20Gy X-irradiation to the right lung, and then were followed for 6 weeks. To validate PP188 treatment does not interfere with RT efficacy to reduce tumor volume, Balb/c mice were implanted with CT26.WT murine colon adenocarcinoma in the high axilla space, given 5Gy SARRP irradiation, and tumor volume was monitored. Rats were evaluated for histopathological changes indicative of acute RILT, including leakage of proteins into alveolar space, thickening of alveolar septa, and alteration of bronchial epithelium and capillaries; for presence of inflammatory infiltrate (Hanker-Yates Peroxidase Leukocyte kit); and for immunohistochemical expression of alpha-smooth muscle actin (SMA). Without PP188, significant inflammatory infiltrate was observed in all lungs bilaterally (p&amp;lt;0.001) contributing to significant bronchiole epithelium thickening (p&amp;lt;0.001) and alveolar septa thickening (p&amp;lt;0.001). Within the thickened alveoli there was significant SMA expression (p&amp;lt;0.001) indicative of cells undergoing a myofibroblast transition that was not observed in the PP188+RT animals or controls. Morphological assessment demonstrated that PP188 significantly attenuated pathological changes in the functional subunits of the lung, alveoli, as well as the vasculature including bronchiole epithelium and small capillaries, with no significant differences from control animals. Finally, it was shown that PP188 does not abrogate radiation-induced tumor volume reduction. The unique mechanism of PP188 provides radioprotection to healthy tissue without interfering with tumor control, and has the potential to mitigate radiation-induced toxicities in the majority of cancers treated with RT. Citation Format: Sarah G. Dennis-Little, Wilfred Ngwa, Marikki Laiho, Graham Warren, Michael J. Yost. Purified poloxamer 188 mitigates radiation-induced lung toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3319.
Abstract 2733: A computational model of cellular metabolism with mutation data predicts metabolites associated with somatic mutations in cancers
Authors: Sang Mi Lee, GaRyoung Lee, Sungyoung Lee, Hyojin Song, Sung Soo Yoon, Hongseok Yun, Youngil Koh, Hyun Uk Kim
Journal: Cancer Research (2022)

Abstract Metabolic reprogramming is considered a hallmark of cancers, which plays an important role in cancer progression and development, partly as a consequence of somatic mutations. A representative product of metabolic reprogramming in cancers is oncometabolites that show abnormal accumulation in a cancer cell, induce malignancy, and are generated upon mutations in a metabolic gene, often IDH1, SDH or FH. Identification of novel mutation-associated metabolites will facilitate developing biomarkers and treatment strategies for cancers, as in the case of ivosidenib, an FDA approved drug for treating acute myeloid leukemia (AML) having the IDH1 mutant. To this end, we develop a computational workflow that predicts so-called metabolite-gene-pathway sets (MGPs) that present metabolites and metabolic pathways significantly associated with gene mutations in cancers. The computational workflow uses cancer patients’ mutation data and a computational model of cellular metabolism called a genome-scale metabolic models (GEM). In this study, the computational workflow was demonstrated using 943 cancer patient-specific GEMs representing 24 different cancer types based on the Pan-Cancer Analysis of Whole Genomes (PCAWG) data [1], which, as a result, predicted 4,135 MGPs for these multiple cancer types. The computational workflow was shown to generate biologically meaningful MGPs on the basis of multi-omics data from 17 AML samples collected in this study as well as previous published studies. For the AML samples, metabolites of the MGPs predicted using the computational workflow showed significantly different intracellular concentrations, depending on mutation of genes involved in the MGP. Moreover, for the 115 MGPs predicted for CNS-GBM/Oligo that are associated with mutation of CIC, EGFR, IDH1 or TP53, 69% of the MGPs were supported by previous studies. This two-level validation indeed showed that it is possible to characterize metabolic pathways and their metabolites that are affected in response to somatic mutations in a cancer cell. Our computational workflow and its prediction outcomes will help better understand the mutation-associated metabolic reprogramming in cancers, and serve as a valuable resource for further extended studies on cancer metabolism. [1] The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82-93 Citation Format: Sang Mi Lee, GaRyoung Lee, Sungyoung Lee, Hyojin Song, Sung Soo Yoon, Hongseok Yun, Youngil Koh, Hyun Uk Kim. A computational model of cellular metabolism with mutation data predicts metabolites associated with somatic mutations in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2733.
Impact of PD-1 Blockade in Nonresponders: Pitfalls and Promise
Authors: Harry H. Yoon, Haidong Dong, Qian Shi
Journal: Clinical Cancer Research (2022)

Summary Exploratory analysis of a phase III trial in esophageal cancer found that the patients who most contributed to an overall survival benefit from PD-1 blockade were not responders, but non-responders. The analysis has limitations but may have implications for investigating the optimal timing of immunotherapy relative to other treatments. See related article by Okada et al., p. 3277
Abstract 1422: A novel agonist of CD137 shows immunoprevention efficacy against various tumors by invoking an innate immune surveillance mechanism
Authors: Haval Shirwan, Lalit Batra, Qingsheng Li, Mohammad T. Malik, Pradeep Shrestha, Nejat Egilmez, Esma S. Yolcu
Journal: Cancer Research (2022)

Abstract Introduction: Immune checkpoints have been the focus of intense research due to their critical roles in regulating immune responses. The CD137 is an immune checkpoint stimulator has pleiotropic immune functions along with its canonical role in driving CD8+ T cell responses. Using a novel form of its natural ligand (SA-4-1BBL) as a single agent, we recently showed its robust cancer immunoprevention efficacy against various transplantable tumor types in mice. In this study, we report its efficacy in a spontaneous tumor model and elucidate the mechanistic basis of prevention. Study design: Mice were treated subcutaneously with SA-4-1BBL protein twice, two weeks apart, and challenged with various tumor types 1-14 weeks later. Animals were monitored for tumor growth. The LSL-KrasG12D mice, as a model of spontaneous lung cancer, were intranasally infected with 2.5 × 107 PFUs of adenoviral-cre to induce cancer. Animals were treated with SA-4-1BBL twice, two weeks apart, pre or post-infection with adeno and euthanized at various times to collect the lung and lymphoid tissues for histopathology and flow cytometry. Results: Pretreatment with SA-4-1BBL was effective in preventing the growth of various transplantable tumors, B16-F10 melanoma, 3LL lung cancer, A20 lymphoma, 4T1 breast cancer, in different mouse strains. Treatment with SA-4-1BBL induced a window of protection against tumors that lasted over 14 weeks. SA-4-1BBL treatment significantly reduced the lung tumor burden in LSL-KrasG12D mice that was associated with increased absolute numbers of CD137+CD4+CD44hi T cells and CD137+NKG2D+NK cells expressing IFN-γ and TNF-α. A blocking antibody to NKG2D reversed the immunopreventive efficacy of SA-4-1BBL in the 3LL and B16-F10 tumor models, providing direct evidence for the role of this receptor in cancer immunoprevention. Gamma/delta T cells did not play a role in the cancer prevention efficacy of SA-4-1BBL as mice lacking these cells showed protection. Conclusions: These results demonstrate that SA-4-1BBL invokes an innate immune surveillance mechanism orchestrated by cross-communication between memory-like CD4+ T cells and NK cells with long-term protection against various tumor types. Funded in parts by NIH R41CA199956, T32HL134644, NCI R25CA134283, and Kentucky KSTC-184-512-16-237 awards. Citation Format: Haval Shirwan, Lalit Batra, Qingsheng Li, Mohammad T. Malik, Pradeep Shrestha, Nejat Egilmez, Esma S. Yolcu. A novel agonist of CD137 shows immunoprevention efficacy against various tumors by invoking an innate immune surveillance mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1422.
Abstract 3949: Identification of a novel HASPIN inhibitor and the synthetic lethal partner by computational analysis
Authors: Eun-Ji Kwon, Karishma Mashelkar, Hyuk Woo Lee, Yoon-Ze Shin, Lak Shin Jeong, Hyuk-Jin Cha
Journal: Cancer Research (2022)

Abstract HASPIN, a mitotic kinase to phosphorylate Histone H3 at centromere, has been studied as a promising target for anti-cancer therapy. However, as HASPIN belongs to atypical kinase, lacking the Asp-Phe-Gly (DFG) motif, development from the chemical library of kinase inhibitors with conventional pharmacophore, would be technically challenging. In particular, one of adenosine analogues (LJ4827), a potent inhibitor of multi-kinases, showing clear anti-cancer activity in vitro and in vivo, was predicted as a HASPIN inhibitor by computation analysis of its transcriptome profile in cancer cells to drug-omic data set in the connectivity MAP (cMAP) as it shared similar transcriptome profile of 5-iodotubercidin (5ITU). The specificity and potency as HASPIN inhibitor of LJ4827 (IC50 = 0.45 nM) validated by in vitro kinase screening and consequent 3D structure modeling. As expected, treatment of LJ4827 in cancer cell lines efficiently delayed mitotic progression without double strand break (DSB) unlike 5ITU and significantly attenuated Aurora B localization at centromere. Along with clinical significance of HASPIN expression in lung cancer patients, mitotic gene signature closely associated to high expression of HASPIN, revealed the poor prognosis. Additional computational analysis of kinase perturbation data to predict the dependency of mitotic kinase in the absence of HASPIN activity, revealed the synthetic lethal effect of cotreatment of the chemical inhibitor of BUB1, PLK1 or AURKA with LJ4827. These data suggest that combined inhibition of HASPIN with the novel inhibitor and key mitotic kinases for centromere/kinetochore regulation would be effectivity therapeutic approach for cancer therapy. Citation Format: Eun-Ji Kwon, Karishma Mashelkar, Hyuk Woo Lee, Yoon-Ze Shin, Lak Shin Jeong, Hyuk-Jin Cha. Identification of a novel HASPIN inhibitor and the synthetic lethal partner by computational analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3949.
Abstract 5294: MDX-124, a novel annexin-A1 antibody, induces significant anti-cancer activity in multiple preclinical models
Authors: Fiona C. Dempsey, Hussein Al-Ali, Scott J. Crichton, Charlene Fabian, Chris Pepper, Bin-Zhi Qian, Xue-Feng Li, Christopher N. Parris
Journal: Cancer Research (2022)

Abstract Annexin-A1 (ANXA1) is secreted from both cancer and immune cells in response to several physiological stimuli and modulates cellular functions through interactions with formyl peptide receptors (FPR1/2). Overexpression of ANXA1 has been observed in multiple cancers, including triple-negative breast (TNBC), colorectal, lung, pancreatic, gastric and prostate, and correlates with poor prognosis and decreased overall survival. ANXA1 has also been shown to promote cancer cell proliferation, angiogenesis, migration and drug resistance, and to modulate the tumor microenvironment. MDX-124 is a novel humanized antibody targeting ANXA1. Previously we presented data demonstrating its significant anti-proliferative activity. Here we provide further data on the mechanism of action of MDX-124, notably its impact on tumor growth, cell cycle arrest and migration in several preclinical cancer models. Incubation of pancreatic (BxPC-3), lung (A549) and TNBC (MDA-MB-231) cancer cell lines with MDX-124 for 24 h decreased the proportion of cells in S-phase by up to 18.3% with a concomitant increase in G1 phase of up to 33.5% versus untreated cells. This effect occurred in a dose-dependent manner and is consistent with an MDX-124 mediated increase in cell cycle arrest. After 72 h incubation with MDX-124, the migratory ability of gastric (AGS), prostate (PC-3), TNBC (MDA-MB-231), lung (A549), pancreatic (MIA PaCa-2) and colorectal (LoVo) cancer cells was significantly reduced in a dose-dependent manner when compared to untreated controls. Proteomic analysis following incubation of MDX-124 with a panel of cancer cell lines for 72 h demonstrated substantial alterations in the level of expression and phosphorylation of multiple key oncogenic proteins. In the MycCaP-Bo syngeneic model of bone metastatic prostate cancer, mice treated with the murine analog of MDX-124 (10 mg/kg, BIW) had a 52% reduction in mean tumor growth after 14 days compared to isotype control treated mice. In conclusion, our data indicate that targeting ANXA1 with MDX-124 inhibits key tumorigenic processes in several clinically challenging cancer indications. MDX-124 therefore provides an innovative approach to cancer therapy. Medannex initiated a First-In-Human study in Q4 2021 to evaluate MDX-124 in solid malignancies known to overexpress ANXA1. Citation Format: Fiona C. Dempsey, Hussein Al-Ali, Scott J. Crichton, Charlene Fabian, Chris Pepper, Bin-Zhi Qian, Xue-Feng Li, Christopher N. Parris. MDX-124, a novel annexin-A1 antibody, induces significant anti-cancer activity in multiple preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5294.
A Dual Barcoding Approach to Bacterial Strain Nomenclature: Genomic Taxonomy of<i>Klebsiella pneumoniae</i>Strains
Authors: Melanie Hennart, Julien Guglielmini, Sébastien Bridel, Martin C J Maiden, Keith A. Jolley, Alexis Criscuolo, Sylvain Brisse
Journal: Molecular Biology and Evolution (2022)

Abstract Sublineages (SLs) within microbial species can differ widely in their ecology and pathogenicity, and their precise definition is important in basic research and for industrial or public health applications. Widely accepted strategies to define SLs are currently missing, which confuses communication in population biology and epidemiological surveillance. Here, we propose a broadly applicable genomic classification and nomenclature approach for bacterial strains, using the prominent public health threat Klebsiella pneumoniae as a model. Based on a 629-gene core genome multilocus sequence typing (cgMLST) scheme, we devised a dual barcoding system that combines multilevel single linkage (MLSL) clustering and life identification numbers (LINs). Phylogenetic and clustering analyses of &amp;gt;7,000 genome sequences captured population structure discontinuities, which were used to guide the definition of 10 infraspecific genetic dissimilarity thresholds. The widely used 7-gene multilocus sequence typing (MLST) nomenclature was mapped onto MLSL SLs (threshold: 190 allelic mismatches) and clonal group (threshold: 43) identifiers for backwards nomenclature compatibility. The taxonomy is publicly accessible through a community-curated platform (https://bigsdb.pasteur.fr/klebsiella), which also enables external users’ genomic sequences identification. The proposed strain taxonomy combines two phylogenetically informative barcode systems that provide full stability (LIN codes) and nomenclatural continuity with previous nomenclature (MLSL). This species-specific dual barcoding strategy for the genomic taxonomy of microbial strains is broadly applicable and should contribute to unify global and cross-sector collaborative knowledge on the emergence and microevolution of bacterial pathogens.
Abstract 2950: Coexpression networks of miRNAs and gene transcripts coinciding with lung adenocarcinoma progression and survival
Authors: Corey D. Young, Eric B. Dammer, Ti'ara L. Griffen, Sha'kayla K. Nunez, Courtney Dill, Kaylin M. Carey, James W. Lillard
Journal: Cancer Research (2022)

Abstract Lung &amp; bronchus cancer is the second most diagnosed cancer, causing the most cancer-related deaths in the United States. A lung and bronchus subtype, NSCLC (non-small cell lung cancer), accounts for over 75% of new lung cancer diagnoses of which lung adenocarcinoma (LUAD) is the most common. Here, we studied the role of microRNAs and the transcriptome expression profile in LUAD prognosis, progression, and overall patient survival. We analyzed RNA-sequence data from a cohort of LUAD patients from The Cancer Genome Atlas (TCGA). The correlations of microRNA gene expression to transcription networks identified by weighted gene co-expression network analysis (WGCNA) were further explored in an upstream regulator/signaling pathway analysis, gene ontology (GO) process enrichment, and differential expression analysis. Mature microRNA abundance was also integrated with the mRNA network via correlation analysis. Our analysis revealed 18 clusters (modules) of highly correlated gene transcripts. The turquoise and red modules were of particular interest, as they were correlated negatively with overall survival, positively with stage 1 status, and negatively to later pathologic stages (3-4). Additionally, high select miRNA correlation to the red module transcripts (e.g., C16Orf89, ADGRF5, CFAP221, and SELENBP1; all with module eigengene correlation rho ≥ 0.75), and to the turquoise module (e.g., DDX39B and LENG8; each with rho ≥ 0.85) suggests these are miRNA-mRNA coregulatory networks of which both the gene products and potentially upstream miRNAs may serve as promising mechanistic targets and prognostic markers for LUAD, meriting further study. Citation Format: Corey D. Young, Eric B. Dammer, Ti'ara L. Griffen, Sha'kayla K. Nunez, Courtney Dill, Kaylin M. Carey, James W. Lillard. Coexpression networks of miRNAs and gene transcripts coinciding with lung adenocarcinoma progression and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2950.
Abstract 655: Macrophage mediated resistance to TKI therapy in ALK fusion positive non-small cell lung cancer
Authors: Melanie Mandell, Katherine Priest, Anh Le, Lynn Heasley, Raphael Nemenoff, Erin L. Schenk
Journal: Cancer Research (2022)

Abstract Patients with lung cancer bearing driver oncogenes such as epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions, often experience long term disease control on targeted therapy. Despite excellent initial responses, ultimately these tumors develop resistance to targeted therapy. While several cancer cell intrinsic mechanisms of targeted therapy resistance are well known, they do not account for all cases of resistance. Based on our previous observations, we hypothesized components of the tumor microenvironment, specifically monocytes and macrophages, also contribute to the development of targeted therapy resistance. We generated bone marrow derived macrophages from C57BL/6 mice and polarized them to an M0, M1, or M2 phenotype over the course of 6 days. At day 7, cells were plated in fresh media and after 2 days, the conditioned media (CM) was collected. Macrophage polarization was verified via qPCR. Murine cell lines, EA-1, EA-2, and EA-3 are unique, murine lung adenocarcinomas bearing an oncogenic ALK fusion derived from C57BL/6 mice. These murine cell lines were then cultured in the macrophage CM prior to exposure to ALK fusion specific tyrosine kinase inhibitors (TKI), alectinib or crizotinib. We observed that culture in M2-CM resulted in at least a 10-fold increase in alectinib resistance across all 3 murine cell lines when compared to the same cell lines cultured in M1 or M0-CM. We next tested for the activity of known, clinically relevant bypass signaling pathways as mediator of M2-CM protection. Aftatinib, an inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2) family of proteins, did not alter M2-CM protection in the presence of alectinib. M2-CM did not impart TKI resistance to the murine cell lines in the presence of crizotinib, a TKI which inhibits ALK fusion activity and MET receptor tyrosine kinase activity, suggesting bypass signaling through MET drives the M2-CM resistance. Ongoing animal model studies demonstrate a clear role for innate immune cells in decreasing tumor responsiveness to TKI. In summary, our work demonstrates TKI therapy may be modulated by the presence of and interaction with specific immune cells within the tumor microenvironment. These data support exploring macrophage targeting therapies to improve TKI responsiveness. Citation Format: Melanie Mandell, Katherine Priest, Anh Le, Lynn Heasley, Raphael Nemenoff, Erin L. Schenk. Macrophage mediated resistance to TKI therapy in ALK fusion positive non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 655.
Distributed learning for heterogeneous clinical data with application to integrating COVID-19 data across 230 sites
Authors: Jiayi Tong, Chongliang Luo, Md Nazmul Islam, Natalie E. Sheils, John Buresh, Mackenzie Edmondson, Peter A. Merkel, Ebbing Lautenbach, Rui Duan, Yong Chen
Journal: npj Digital Medicine (2022)

Integrating real-world data (RWD) from several clinical sites offers great opportunities to improve estimation with a more general population compared to analyses based on a single clinical site. However, sharing patient-level data across sites is practically challenging due to concerns about maintaining patient privacy. We develop a distributed algorithm to integrate heterogeneous RWD from multiple clinical sites without sharing patient-level data. The proposed distributed conditional logistic regression (dCLR) algorithm can effectively account for between-site heterogeneity and requires only one round of communication. Our simulation study and data application with the data of 14,215 COVID-19 patients from 230 clinical sites in the UnitedHealth Group Clinical Research Database demonstrate that the proposed distributed algorithm provides an estimator that is robust to heterogeneity in event rates when efficiently integrating data from multiple clinical sites. Our algorithm is therefore a practical alternative to both meta-analysis and existing distributed algorithms for modeling heterogeneous multi-site binary outcomes.